1. Field of the Invention
The present invention relates to new macrocyclic ketone, hydroxy and hydroxyketone compounds and to melanin synthesis inhibitors containing such compounds. The present invention also relates to an external skincare agent containing one or at least two kinds of such melanin synthesis inhibitors.
2. Description of Background Information
Ultra violet rays and other forms of irradiation cause tanning. The colour change (tanning) of the skin tissue has its origin in melanin synthesis and the stagnation of the melanin inside the pigmented cells under the influence of hormones and stimulation by ultraviolet exposure. Freckles, wrinkles and the like are formed by the stagnation and the fixation of melanin inside the surface layer of the skin at some places.
As regards melanin synthesis on the skin surface, tyrosinase, which is an oxidative enzyme synthesised in the pigmented cells, oxidizes and polymerises tyrosine thus synthesising melanin.
There is much research into ways of inhibiting melanin synthesis and its fixation process in order to create a cosmetic whitening agent.
Until now, vitamin C, cysteine, kojic acid, arbutin, glutathione, hydroquinone and other efficient compounds extracted from natural substances are known for inhibiting melanin synthesis by lowering the tyrosinase activity or by bleaching and lightening the colour of the synthesised melanin. However, the stability, safety and whitening effect of these compounds are not sufficient, and no satisfactory whitening agent has been obtained until now.
Moreover, until now, 2-hydroxycyclopentadecanone, which is an intermediate compound in the synthesis of musk fragrance, and which has a macrocyclic hydroxyketone structure comprising a 15 carbon atom ring, is known to be an inhibitor of melanin synthesis having a macrocyclic hydroxyketone structure (JP-A-Hei-9-151129). However, the melanin synthesis inhibiting action of this compound is not sufficient and the development of inhibitors of melanin synthesis having a high activity is still desired.
In U.S. Pat. No. 6,200,254, xcex1-hydroxyketones are disclosed as intermediate compounds in the synthesis of macrocyclic dieneketone compounds of the following chemical Formula (4a) 
(wherein R1, R2, R3 and R4 are hydrogen atom or an alkyl group of 1 to 4 carbon atoms, respectively, xe2x80x9caxe2x80x9d being equal to 1 or 2, and xe2x80x9cbxe2x80x9d being equal to any one of 1 to 6) and the saturated or monounsaturated macrocyclic ketone compounds of Formula (4b) 
(wherein R1, R2, R3 and R4 are hydrogen atom or an alkyl group of 1 to 4 carbon atoms, respectively, xe2x80x9caxe2x80x9d being equal to 1 or 2 and b being equal to any one of 1 to 6).
Further, macrohydroxyketones comprising a ring of more carbon atoms, for example 2-hydroxycyclodocosanone which comprises a 22 carbon atom ring and 2-hydroxycyclotetracosanone which comprises a 24 carbon atom ring are known as intermediate compounds in the synthesis of [20.3.3]propelan-24,27-dione and [22.3.3]propelan-26,29-dione respectively (see Helv. Chim. Acta, 68, 2033 (1985), J. Am. Chem. Soc., 109, 7477(1987)).
Moreover, 2-hydroxycyclotetracosanone which comprises a 24 carbon atom ring is known as a precursor of trans-tetracosan-1, 2-semidione used in configuration analysis (J. Am. Chem. Soc., 107, 1717(1985)). 2-hydroxycyclohexacosanone comprising a 26 carbon atom ring is known as a compound synthesised via acyloin cyclization reaction of diethyl 1,26-hexacosanedioate (Ann. Chim. (Rome), 60(2), 155(1970)).
Further, 2-hydroxycyclooctacosanone which comprises a 28 carbon atom ring and 2-hydroxycyclotriacontanone which comprises a 30 carbon atom ring are reported as used in the construction of a part of the macrocyclic ring of shuttle molecules. (Chem. Ber., 113, 941, 1980; J. Am. Chem. Soc., 89, 5723, 1967).
However, as to macrocyclic compounds comprising a ring of 13 to 19 carbon atoms and of more than 22 carbon atoms, there is no mention of the specificity of xcex1-hydroxyketone groups. Consequently, the macrocyclic xcex1-hydroxyketone compounds comprising a ring of 16 to 26 carbon atoms, were not at all expected to have any activity as melanin synthesis inhibitor.
An object of the invention is to provide on the one hand an inhibitor of melanin synthesis which has excellent safety and stability, and which has a high inhibiting action on melanin synthesis, and on the other hand an external skincare product containing such an inhibitor.
To this end, there is provided a melanin-synthesis inhibitor composition containing at least one macrocyclic compound represented by Formula (1) 
wherein X signifies a group selected among the groups consisting of xe2x80x94COxe2x80x94, xe2x80x94CHOHxe2x80x94 and xe2x80x94COxe2x80x94CHOHxe2x80x94; R signifies a chain hydrocarbon having 13 to 24 carbon atoms and forming a ring with X; and R either is saturated or contains 1 to 3 unsaturated bonds, and may be substituted with a lower alkyl group of 1 to 3 carbon atoms, with the proviso that, when X is xe2x80x94COxe2x80x94CHOHxe2x80x94, the number of carbon atoms in said chain hydrocarbon is not 13; and, optionally, an appropriate ingredient and/or medium.
Typically, in the melanin-synthesis inhibitor compositions of the invention, X signifies a xe2x80x94COxe2x80x94 group.
Such compositions may contain at least one compound selected from the group consisting of cyclotetradecanone, cyclopentadecanone, cyclohexadecanone, cycloheptadecanone, cyclooctadecanone, cyclononadecanone, cycloeicosanone, cycloheneicosanone, cyclodocosanone, cyclotricosanone, cyclotetracosanone, cyclopentacosanone, 3-methylcyclopentadecanone, (S)-3-methylcyclopentadecanone, (R)-3-methylcyclopentadecanone, 3-methylcyclohexadecanone, 4-methylcyclohexadecanone, 4-cyclopentadecenone, 5-cyclopentadecenone, 4-cyclohexadecenone, 5-cyclohexadecenone, (E)-5-cyclohexadecenone, (Z)-5-cyclohexadecenone, 9-cyclopentadecenone, (E)-9-cyclopentadecenone, (Z)-9-cyclopentadecenone, 3-methyl-4-cyclopentadecenone, 3-methyl-5-cyclopentadecenone, 3-methyl-4-cyclohexadecenone, 3-methyl-5-cyclohexadecenone, 4-methyl-4-cyclohexadecenone, 4-methyl-5-cyclohexadecenone, 10-cycloeicosenone, 11-cyclodocosenone and 12-cyclotetracosenone.
Alternatively, in the melanin-synthesis inhibitor compositions of the invention, X signifies a xe2x80x94CHOHxe2x80x94 group.
Such compositions may contain at least one compound selected from the group consisting of cyclotetradecanol, cyclopentadecanol, cyclohexadecanol, cycloheptadecanol, cyclooctadecanol, cyclononadecanol, cycloeicosanol, cycloheneicosanol, cyclodocosanol, cyclotricosanol, cyclotetracosanol, cyclopentacosanol, 3-methylcyclopentadecanol, (1R, 3R)-3-methylcyclopentadecanol, (1R, 3S)-3-methylcyclopentadecanol, (1s, 3R)-3-methylcyclopentadecanol, (1s, 3S)-3-methylcyclopentadecanol, 3-methylcyclohexadecanol, (4-methylcyclohexadecanol, 4-cyclopentadecenol, 5-cyclopentadecenol, 4-cyclohexadecenol, 5-cyclohexadecenol, (E)-5-cyclohexadecenol, (S)-5-cyclohexadecenol, 9-cycloheptadecenol, (E)-9-cycloheptadecenol, (S)-9-cycloheptadecenol, 3-methyl-4-cyclopentadecenol, 3-methyl-5-cyclohexadecenol, 4-methyl-4-cyclohexadecenol, 4-methyl-5-cyclohexadecenol, 10-cycloeicosenol, 11-cyclodocosenol and 12-cyclotetracosenol.
Preferably, the melanin synthesis inhibitor compositions contain at least one macrocyclic compound of Formula (1) where X signifies group xe2x80x94COxe2x80x94, and at least one macro cyclic compound of Formula (1) where X signifies group xe2x80x94CHOHxe2x80x94.
Alternatively yet, in the melanin synthesis inhibitor compositions of the invention, X signifies a xe2x80x94COxe2x80x94CHOHxe2x80x94 group, R being a chain hydrocarbon having 14 to 24 carbon atoms.
Such compositions may contain at least one compound selected from the group consisting of 2-hydroxycyclohexadecanone, 2-hydroxycycloheptadecanone, 2-hydroxycyclooctadecanone, 2-hydroxycyclononadecanone, 2-hydroxycycloeicosanone, 2-hydroxycycloheneicosanone, 2-hydroxycyclodocosanone, 2-hydroxycyclotricosanone, 2-hydroxycyclotetracosanone, 2-hydroxycycloheptacosanone, 2-hydroxycyclohexacosanone, 2-hydroxycyclo-3-methylcycloeicosanone, 2-hydroxy-20-methylcycloeicosanone, 2-hydroxy-4,19-dimethylcycloeicosanone, (4R)-2-hydroxy-4-methylcycloeicosanone, (19R)-2-hydroxy-19-methylcycloeicosanone, 2-hydroxy-8-cyclohexadecenone, 2-hydroxy-9-cycloheptadecenone, 2-hydroxy-10-cyclooctadecenone, 2-hydroxy-10-cyclononadecenone, 2-hydroxy-11-cycloeicosenone, (Z)-2-hydroxy-11-cycloeicosenone, (E)-2-hydroxy-11-cycloeicosenone, 2-hydroxy-10-cycloheneicosenone, 2-hydroxy-11-cyclodocosenone, 2-hydroxy-13-cyclotetracosenone, 2-hydroxy-3-methyl-11-cycloeicosenone, 2-hydroxy-20-methyl-11-cycloeicosenone, 2-hydroxy-4,19-dimethyl-11-cycloeicosenone, (4S)-2-hydroxy-4-methyl-11-cycloeicosenone, (19S)-2-hydroxy-19-methyl-11-cycloeicosenone, (5E, 15E)-2-hydroxy-5,15-cyclooctadecadienone, (5E, 17E)-2-hydroxy-4,19-dimethyl-5,17-cycloeicosadienone,
Preferably, R is a chain hydrocarbon having 16 to 22 carbon atoms.
Preferably yet, R is a chain hydrocarbon having 18 or 19 carbon atoms.
Such compositions may contain at least one compound selected from the group consisting of 2-hydroxycycloeicosanone, 2-hydroxycycloheneicosanone, 2-hydroxy-11-cycloeicosenone, 2-hydroxy-11-cycloheneicosenone and 2-hydroxy-12-cycloheneicosenone.
The invention also relates to an external skincare product, characterised in that it contains at least one composition as defined above.
Preferably, the skincare product contains at least one composition defined above in a concentration ranging from 0.00001 to 10 weight %.
The invention further relates to a macrocyclic compound represented by Formula (1): 
wherein X signifies a xe2x80x94COxe2x80x94CHOHxe2x80x94 group; R signifies a chain hydrocarbon having 18 or 19 carbon atoms and forming a ring with X; and R either is saturated or contains 1 to 3 unsaturated bonds, and may be substituted with a lower alkyl group of 1 to 3 carbon atoms.
Such a macrocyclic compound may be selected from the group consisting of 2-hydroxycycloeicosanone, 2-hydroxycycloheneicosanone, 2-hydroxy-11-cycloeicosenone, 2-hydroxy-11-cycloheneicosenone and 2-hydroxy-12-cycloheneicosenone.
Typically, the above macrocyclic compound is prepared by a method comprising the steps of:
preparing a corresponding unsaturated chain hydrocarbon having 20 or 21 carbon atoms, whose both end carbons form esterified carboxy groups;
subjecting said esters to an acyloin condensation, so that an unsaturated macrocyclic compound is obtained; and optionally,
subjecting said unsaturated macrocyclic compound to subsequent hydrogenation.
The invention further concerns a process of inhibiting a melanin synthesis using a compound of Formula (1) defined above.
Methyl, ethyl, n-propyl and isopropyl groups may be given as examples of lower alkyl group having 1 to 3 carbon atoms.
The invention will be explained in more detail on the basis of the following examples of synthesis of compounds according to the invention and of results regarding the melanin synthesis inhibiting effect of the compounds of the present invention.
The above, and other objects, features and advantages of the invention will be made apparent from the following description of the preferred embodiments, given as non-limiting examples.